Back to Search
Start Over
Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice
- Source :
- eLife, Vol 10 (2021), eLife
- Publication Year :
- 2021
- Publisher :
- eLife Sciences Publications Ltd, 2021.
-
Abstract
- Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
- Subjects :
- 0301 basic medicine
Male
Parkinson's disease
Mouse
mito-QC
kinase inhibitor
QH301-705.5
Science
Mice, Transgenic
Mitochondrion
Biology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Mice
0302 clinical medicine
Gene knockin
Mitophagy
medicine
Animals
Kinase activity
Biology (General)
Mice, Knockout
General Immunology and Microbiology
Kinase
General Neuroscience
Autophagy
Parkinson Disease
LRRK2
General Medicine
Cell Biology
medicine.disease
Cell biology
nervous system diseases
030104 developmental biology
Mutation
parkinson's disease
Medicine
Female
030217 neurology & neurosurgery
Research Article
Neuroscience
Subjects
Details
- Language :
- English
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....6415a524a8c36dd76f9496bbe9760360